Apellániz-Ruiz, MaríaTejero, HéctorInglada-Pérez, LucíaSánchez-Barroso, LaraGutiérrez-Gutiérrez, GerardoCalvo, IsabelCastelo, BeatrizRedondo, AndresGarcía-Donás, JesúsRomero-Laorden, NuriaSereno, MaríaMerino, MaríaCurrás-Freixes, MaríaMontero-Conde, CristinaMancikova, VeronikaÅvall-Lundqvist, ElisabethGreen, HenrikAl-Shahrour, FatimaCascón, AlbertoRobledo Batanero, MercedesRodríguez-Antona, Cristina2024-02-062024-02-062017-03-01Clin Cancer Res . 2017 ;23(5):1227-1235.http://hdl.handle.net/20.500.12105/17507Purpose: Neuropathy is the dose-limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for interindividual differences remain unexplained. In this study, we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.Experimental Design: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics, and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high-grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/gene-based analyses were used to compare variant frequencies among neuropathy groups, and Cox regression models were used to analyze neuropathy along treatment.Results: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in EPHA6 were present exclusively in patients with high neuropathy, and all affected the ligand-binding domain of the protein. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency nonsynonymous variant carriers [HR, 14.60; 95% confidence interval (CI), 2.33-91.62; P = 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14-3.77; P = 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46-4.31; P = 9.1 × 10-4).Conclusions: This first study sequencing EPHA genes revealed that low-frequency variants in EPHA6, EPHA5, and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs. Clin Cancer Res; 23(5); 1227-35. ©2016 AACR.engAMhttp://creativecommons.org/licenses/by-nc-nd/4.0/AdultAgedBiomarkers, PharmacologicalBreast NeoplasmsFemaleGenetic Association StudiesHumansMiddle AgedOvarian NeoplasmsPaclitaxelPeripheral Nervous System DiseasesPolymorphism, Single NucleotideProportional Hazards ModelsQuality of LifeReceptor, EphA5Receptor, EphA6Receptor, EphA8Attribution-NonCommercial-NoDerivatives 4.0 Internacional27582484235122710.1158/1078-0432.CCR-16-06941557-3265Clinical cancer research : an official journal of the American Association for Cancer Researchopen access